17alpha-alkynyl-2beta-halo-5alpha-androstane-3alpha, 17beta-diols, esters thereof, and intermediates thereto



United States Patent ()fiice 3,098,851 Patented July 23, 1963 The present invention relates to novel steroidal halohydrins and, more particularly, to '17oc-31KY11Yl-2B-h3lO-5ocandrostane-3a,l7/3-diols and the corresponding ester-s, which are represented by the structural formula R C I :-(lower alkynyl) wherein X is a halo radical and R and R can be hydrogen or a lower alkanoyl radical.

The halo radicals represented by X are fluoro, chloro, bromo, and iodo.

Examples of the lower alkanoyl radicals indicated in the structural representation supra are ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the branched-chain isomer-s thereof. The lower alkanoyl radicals encompassed by the R and R terms are, typically, formyl, acetyl, propionyl, butyryl, Valery-l, caproyl, and the branched-chain radicals isomeric therewith.

The compounds of this invention are conveniently prepared by utilizing 3B-p-toluenesu1fonoxy-5a-androstan-17- one, disclosed by Iriarte, Rosenkranz, and Sondheirner at J. Org. Chem., 20, 542 (1955), as the starting material. Heating a solution of that substance at the reflux temperature in a high boiling solvent such as collidine results in a-androst-2-en-l7-one. The reaction of this ketone with a lower l-alkyne affords the corresponding 17u-alkynyl- 17fi-ols, which are epoxidized, typically,.by means of perbenzoic acid to yield the novel Zot,3oc-pOXideS of this invention. The reaction of these epoxides with the appropriate hydrogen halide results in the instant 2fi,3a-halohydrins. These processes are typified by the reaction of the aforementioned 5a-androst-2-en-l7-one with acetylene in the presence of potassium hydroxide to afford 17a-ethynyl- 5u-androst-2-en-17fi-ol, treatment of the latter substance with perbenzoic acid in benzene, resulting in 2a,3ot-epoxy- 17a-ethynyl-hendrostan-l7,8-ol, and the reaction of that epoxide in chloroform with concentrated hydrochloric acid to afford Zfi-chloro17a-ethynyl-5ct-androstane-ila,17,8-diol.

Acylation of the aforementioned 17a-alkynyl-5ot-androst-2-en-17B-ols, typically with a lower alkanoic acid anhydride in pyridine produces the corresponding 17- (lower alkanoates), which are submitted to the hereinbefore described processes to yield the instant novel 170calkynyl-Z/i-halo 5a androstane-3a,17{3-diol 17-mono- (lower alkanoates). For example, 17a-ethynyl-5a-androst-2-en-17B-ol is heated at steam bath temperature with acetic anhydride and pyridine, resulting in 17a-ethynyI-Sa-andrQst-Z-en-175-01 17-acetate. Epoxidation with perbenzoic acid in benzene produces 2a,3a-epoxy-l7aethynyl-5a-androstan-17,8-01 17-acetate, which is allowed to react with hydrobro-rnic acid in chloroform to yield 26- bromo-17ct-ethynyI-Su-androstane-3a,17[3-diol l7-acetate.

Treatment of the instant 30,17fi-di0l5 with a limited quantity af acylating agent at room temperature affords the 3'-mono-(lower alkanoates) of this invention, while reaction at elevated temperature with excess reagent produces the instant 3,17-di-(lower alkanoates). Thus, the aforementioned ZB-chloro-17a-ethynyl-5a-androstane-Zm, 17/3-diol, when treated with acetic anhydride in pyridine by the latter processes, yields the corresponding 3-monoacetate and 3,17-diacetate, respectively. The 3,17-di- (lower alkanoates) can be prepared, alternatively, by heating with the appropriate isopropenyl ester in the presence of an acid catalyst such as p-toluenesulfonic acid. The diacetates, for example, are produced when the acylating agent is isopropenyl acetate. Acylation of the 17-mono- (lower alkanoates) at room temperature also produces the instant 3,17 -di-(lo-wer alkanoates).

The 2a,3ot-epoxides and 2B,3a-halohydrins of this invention are useful as a result of their valuable pharmacological properties. They are, for example, estrogenic agents which lack androgenic and anabolic side-effects. The halohydrins are also hypocholesterolemic agents as is evidenced by their ability to inhibit the hepatic synthesis of cholesterol. The epoxides are, of course, useful also as intermediates in the manufacture of the instant halohydrins. i

This application is a continuation-in-part of our copending application, Serial No. 33,949, filed June 6, 1960, now Patent No. 3,009,934.

The invention will appear more fully from the examples which follow. These examples are set forth by way of illustration only, and it will be understood that the invention is not to be construed as limited in spirit or in scope Example 1 A mixture of 5 parts of 3fl-p-toluenesulfonoxy-Sa-androstan-l7-one and 350 parts of purified collidine is stirred and heated at reflux for about 4 hours. This reaction mixture is cooled, then treated with ice and 500 parts by volume of l N sulfuric acid. The resulting mixture is extracted with ether, and the organic layer is washed successively with ice-cold l N sulfuric acid, aqueous sodium bicarbonate and water. This washed solution is dried and decolorized over a mixture of anhydrous sodium sulfate and decolorizing carbon, then evaporated to dryness to afford 5u-androst-en-17-one, M.P. 103-105". Recrystallization from methanol affords a pure sample, M.P. 105-1065"; [a] +163 (chloroform).

Example 2 A solution of 950 parts of diethylene glycol dimethyl ether and 66 parts of diethylene glycol monomethyl ether is heated, under nitrogen, to about then treated portionwise with parts of potassium hydroxide over a period of about 1 /2 hours. The solution is allowed to cool slowly to room temperature, then is cooled further to about 0. To this mixture is added successively acetylene for about 2 /2 hours, then a solution of 50 parts of SOL-KHdIrOSt-Z-CH-I l-OIIC in parts of diethylene glycol dimethyl other over a period of about 1 /2 hours. Cooling and acetylene addition are continued for about 2 /2 hours longer, after which time the reaction mixture is diluted with 450 parts of water. "The diluted solution is acidified with ice-cold dilute hydrochloric acid, and the resulting precipitate is collected by filtration and washed with water. The washed precipitate is dissolved in benzone, and the benzene solution is dried over anhydrous potassium carbonate containing decoloriz ing carbon, then is chromatographed on a silica gel column. Elution with 40% petroleum ether in benzene followed by recrystallization from acetone-hexane affords 17a-ethynyl-5a-androst-2-en-17fl-ol, M.P. about 172-174.

Example 3 A solution of 6 parts of =1-butyne and 40 parts of cold other is added plortionwise, in the course of 30 minutes, to a solution of butyl lithium, prepared from 17.3 parts of 1-brornobutane and 2.2 parts of lithium wire in 27 parts of ether. After completion of the addition, the mixture is stirred for 90 minutes at To this solution of butynyl lithium in ether is added, in the course of about 30 minutes, 9.5 parts of a-androst-2-en-17-one in 100 parts of tetrahydrofuran in small portions. After completion of the addition, the ether is removed by distillation, but the volume is maintained essentially constant by replacing the ether with tetrahydrofuran. The resulting mixture is heated at reflux for about 3 hours, then is poured into Water, and the aqueous mixture is cooled by means of an ice-bath. The oily layer which forms is separated, dissolved in ether, and this organic solution is washed successively with water and saturated aqueous sodium chloride, then is dried over anhydrous sodium sulfate, and is finally evaporated to dryness in vacuo to afford 17x-(l-butynyl)-5a-androst-2-en-17,8-01.

Example 4 A solution of parts of 17a-ethynyl-5x-androst-2-en- 175-01 in 325 parts by volume of 0.3 N perbenzoic acid in benzene is stored at 3 for about hours. The precipitate which forms is collected by filtration, washed successively with benzene and with hexane, then dried to afford :,3a-epoxy-17a-ethynyl-5a-androstan-17,8-01, M.P. about 238-240. The filtrate is washed successively with concentrated aqueous sodium carbonate and water, then dried over anhydrous potassium carbonate containing decolorizing carbon and evaporated to dryness in vacuo to afford a further quantity of the product. These two crops are combined and recrystallized from acetone to produce a pure sample of the epoxide, M.P. about 237239. It is represented by the structural formula CH3 :L--CECH Example 5 The substitution of 10.94 parts of 17a-(1-butynyl)-5aandrost-2-en-17fi-ol in the procedure of Example 4 results in 170t-(1-bUtyI1y1) 20,3oc epoxy-Sa-androstan-1713-01, which is represented by the structural formula on CH3 i' --o -=ooH2oH3 a I H Example 6 To a solution of 5 parts of 20,3oc-epoXY-l'loc-ethYIlYl-Saandrostan-17/3-ol in 450 parts of chloroform is added 156 parts of concentrated hydrochloric acid, and the heterogeneous mixture is shaken at room temperature for about 17 minutes. The organic layer is separated, washed with dilute aqueous sodium bicarbonate, then dried over anhydrous potassium carbonate containing decolorizing carbon. This solution is stripped of solvent at reduced pressure to afford an oil, which solidifies on standing. Recrystallization from aqueous methanol produces 25-chloro-17a-ethynyl-5u-androstane-3a,17B-iol, M.P. about 105409". It is represented by the structural formula Example 8 To a solution of 1.4 parts of 2a,3m-epoxy-17a-ethynyl- 5 0t-3I1dTOStaIl-17B-Ol in parts of chloroform is added 27 parts of 48% hydriodic acid, and this two-phase system is stirred rapidly at room temperature for about 20 minutes. The organic layer is then separated, washed successively with water and dilute aqueous sodium bicarbonate, dried over anhydrous potassium carbonate containing decolorizing carbon, and concentrated to dryness in vacuo. The glassy residue is crystallized from acetone-hexane to afford the acetonate of 17a-ethynyl-2fl-iodo-Sa-androstane-Sa, 17Bdiol, M.P. about 141142 (dec.), which is represented by the structural formula CHa OH -OEOH o I- ll CH3C-CH Example 9 ilnto a mixture of 34 parts of tetrahydrofuran and 21 parts of chloroform, cooled to about -70, is bubbled 20.8 parts of anhydrous hydrogen fluoride. To this solution, with stirring and cooling by means of an ice-bath, is added, over a period of about 2 /2 hours, a solution of 10 parts of 2u,3a-epoxy-l7a-ethynyl-5m-androstan-17fi-ol in 96 parts of chloroform. Anhydrous hydrogen fluoride is bubbled slowly through the reaction mixture during the v r g latter addition. Stirring iscontinued for about 1 /2 hours after the addition is complete, during which time the mixture is allowed to warm to room temperature. This solution is poured cautiously into excess concentrated aqueous potassium carbonate, and the resulting aqueous mixture is extracted with chloroform. The organic layer is separated, washed successively with water, dilute aqueous sodium bicarbonate, and water, dried over anhydrous potassium carbonate containing decolorizing carbon, and concentrated to dryness. The residual yellow oil is chromotographed on a silica gel column. El-ution with benzene ethyl acetate followed by recrystallization from acetonehexane produces 17a-ethynyl-2p-fiuoro-5a-androstanc-3a, 17,8-diol, which exhibits maxima in the infrared at about 2.75, 3.01, 3.41, and 9.68 microns. It is represented by the structural formula H3 oson Example 10 The substitution of 5.45 parts of 17u-(1 butynyl)-2u, 30t-BPOXY-Sot-ZlfldlOStSll-1713-01 in the'procedure of Example 6- results in 17a-( l-butynyl)-2[3-ohlono5ot-androstane- 30,17B-di0l, which is represented by the structural formula Example 11 A mixture of parts of 2B-chloro-l7a-ethynyl-5aantroStane-Bu,17,8-diol, parts of acetic anhydride, and 100 parts of pyridine is allowed to stand at room temperatune "for about 8 hours, then is poured slowly into a mixture of ice and water. The resulting precipitate is collected by filtration and dried to afford 3ot-acetoxy-2B- chloro-17a-ethynyl 5a androstan-UB-ol. It is represented by the structural formula OH CH3 i' --ozon 6 17u-ethynyl-3ot-propionoxy-5a-androstan-UB-ol, which is represented by the stuuctural formula OH :'---ozcn OHaCHzC O O- Example 13 To a solution of one part of 2'li-chloro-l7a-ethynyl- 5a-androstane-3a,1713-diol in 20 parts of isopnopenyl ace-- 0 O OCH; CH3 i 050B CHaCOO' Example 14 The reaction of 8.9 parts of 2fl-chloro-l7a-ethynyl-5a- 3.11dPOSt2tI16-3ot,17B-rdi0l,22713211128 of isopropenyl propiohate, and 1.5 parts of p-toluenesulfionic acid monohydrate according to the procedure of Example 13 results in propionate, which is represented by the structural formula 0C 0 01120113 CH CHsCH2COO-- Example 15 A mixture of one part of 17 a-ethynyI-Sa-androst-Z-en- 1713-01, 10 parts of acetic anhydride, and 20 parts of pyridine is heated on the steam bath for about 4 hours, then is cooled and poured into water. The resulting precipitate is collected by filtration, then is dried and recrystallized from hexane to afford 17ot-ethynyl-5a-androst-2-en-17B-o1 17-acetate, M.P. about 119-121". is represented by the structural formula C 0 CH Example 1 6 'Ilhe substitution of 13 parts of propionic anhydride in the procedure of Example 15 results in 17a-ethyny1- a-androst-2-en-17/3-ol 17-propionate.

Example 17 The substitution of 11.4 parts of 17a-ethynyl-5a-androst-2-en-l7fl ol 17-acetate in the procedure of Example 4 results in 2a,3a-epoxy-17m-ethynyl-5a-androstan-175-01 17-acetate.

Example 18 By substituting 11.9 parts of 17a-ethyny1-5a-arrdrost-2- en-17/3-o1 17-propionate in the procedure of Example 4, 2a,3a-epoxy-17a-ethynyl-5a-androstan-175-01 17-prorpionate is obtained.

Example 19 The substitution of 5.67 parts of 2oz,3oc-6p0Xy-l7ocethynyJ-Sa-andrOstan-1713-01 17-acetate in the procedure of Example 6 results in 2,8-ohloro-l7a-ethynyl-5a androstane-3u,17B-diol 17-acetate, which is represented by the structural formula 0 c 0 CH CH3 :I-"CECH Example 20 The substitution of 1.18 parts of 2a,3a-epoxy-17uethyny1-5a-and1'ostan-17fi-o1 17-propionate in the procedure of Example 7 results in 2,6-bromo-17u-ethynyl-5aandrostane-3a,17B-dliol 17-propionate, which is represented by the structural formula 0 C O CHzCHs CH3 8 Example 21 The substitution of 1.09 parts of 17a-(1-butynyl)-5a- 1androst-2-en-17B-o1 in the procedure of Example 15 results in 17oc-( l-butynyl) -5 a-andrOst-Z-en- 17 ,6-01 17-acetate.

Example 22 By substituting 12.3 parts of 17a-(1-butyny l)-5a-androst-2-en-l7 8-ol 17-acetate and otherwise proceeding ac cording to the processes of Example 4, 17u-(1-butynyl)- 20:,3a-epoxy-Sa-androstan-1718-01 17-acetate is obtained.

Example 23 By substituting 6.12 parts of 17a-(1-butyny1)-2a,3uepoxy-5a-androstan-17fl-ol 17-acetate and otherwise proceeding according to the processes of Example 6, 17oc-(lbutynyl) -2fi-chloro-5 a-andIostane-B 0517134101 17-acetate is obtained.

Example 24 The substitution of 5.4 parts of 17zx-(1-butynyl)-2fichloro-5a-androstane-3a,17fi-dio1 in the procedure of Ex ample 11 results in 3a-acetoxy-17a-(l-butynyl)-2,B-chloro- SewandIOStElIl-IZB-Ol.

Example 25 O R CH3 -(lower alkynyl) X wherein X is a halo radical and R and R are selected from the group consisting of hydrogen and lower al-kanoyl radicals.

2. A compound of the structural formula 0 H CH3 j (lower alkynyl) wherein X is a halo radical.

. 2fl-ch1oro-17a ethynyl-5a-androstane-3a,17fl-diol. ZB-bromo-17a-ethynyl-5a-tandrostane-3a,17/3-diol. 17a-ethynyl-2Bdodo-5 a-androstane-ll 0:,175-(1101.

. 17u-ethynyl-2fi fluoro-5a-androstane-3a,17{3-diol. 2a,3a-epoxy-17a-ethynyl-5u-androstan-173-01.

References Cited in the file of this patent UNITED STATES PATENTS 2,996,524 Huifm an Aug. 15, 1961 

1. A COMPOUND OF THE STRUCTURAL FORMULA 